Alpha-Adrenergic

Blockers

Dr. Hiwa K. SaaedPh.D. Pharmacology

& Toxicology

Receptor Tissues Response

α1Eye-radial (dilatory) muscle

Contacts (mydriasis)

Most vascular smooth muscle

-Arterioles (skin, viscera)-veins

Contraction↑TPR→↑ diastolic pressure ↑afterload↑ venous return→↑ preload

Bladder trigone and sphincter

Contraction→urinary retention

Male sex organs Vas deferens→ ejaculation

Liver (in some species, rat )

Stimulate glycogenolysis

Kidney ↓ rennin releasePilomotor smooth muscle

Contraction (erect hair)

Receptor

tissue Response

α 2Adrenergic & cholinergic Prejunctional nerve terminals

↓ transmitter release and NE synthesis

Platelets Stimulate Aggregation

Pancreas (β cells) Inhibit insulin release

Some vascular smooth muscle Contracts

Fat cells Inhibits lipolysis

Medullary vasomotor center ↓sympathetic outflow → CO & vasodilation→↓ BP

Localization of 1-Adrenergic Receptors

Like the agonists, the adrenergic antagonists are classified according to their relative affinities for α1 or α2 receptors .

Drugs that block α-adrenoceptors profoundly affect blood pressure, resulting in decreased peripheral vascular resistance.

Because normal sympathetic control of the vasculature occurs in large part through agonist actions on α-adrenergic receptors

This induces a reflex tachycardia resulting from the lowered blood pressure.

Alpha-Adrenergic Blockers

Alpha-Adrenergic Blockers Classification

I. Type of blockade1. Irreversible (non-competitive) :

Phenoxybenzamine; slow onset and long duration.

2. Reversible (competitive): All the restII. Selectivity: α1 or α2 receptors .

-Nonselective: Phenoxybenzamine and

phentolamine-Selective: 3. alpha-1 selective: Prazosin, terazosin, others 4. alpha-2 selective: Yohimbine 5. alpha/beta blockers: Labetalol -Others: phenothiazines, haloperidol, tricyclic

antidepressants trazodone

α Antagonists Receptor Affinity

Prazosin, terazosin, doxazosin α1>>>>α2

Phenoxybenzamine α1>α2

Phentolamine α1=α2

Rauwolscine, yohimbine, tolazoline α2>α1

Mixed antagonists

Labetalol, carvedilol β1=β2≥α1>α2

Alpha-Adrenergic BlockersNonselective

– Phenoxybenzamine (3-4 days)

Selective• Short-acting selective a1-blocker

– Prazosin t1/2 3 hrs, Alfuzosin t1/2 5 hrs

• Long-acting selective a1-blockers– Terazosin t1/2 9-12 hrs– Doxazosin t1/2 22 hrs

• Long-acting selective a1A-subtype– Tamsulosin t1/2 9-15 hrs

Pharmacological Effects - Phenoxybenzamine

1. Cardiovascular system• ↓PR: ↓ Blood pressure: reflex

tachycardia: • Furthermore, the ability to block

presynaptic inhibitory α2-receptors in the heart will result in more norepinephrine release, which stimulates β- receptors on the heart to increase cardiac output.

• It reduces BP when sympathetic tone is high upright posture, reduced blood volume

Adrenergic System - Antagonists

Epinephrine reversal:

• All α-adrenergic blockers reverse the α-agonist actions of epinephrine. the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of β2 receptors is not blocked.

• Therefore, the systemic blood pressure decreases in response to epinephrine given in the presence of phenoxybenzamine. ….Why?

• The actions of norepinephrine are not reversed but are diminished, …why?

Pharmacological Effects – Phenoxybenzamine

2. Eye – miosis3. Nasal stuffiness4. GI tract – Increased motility5. Urinary bladder – decreased tone in

sphincter6. Metabolic effects – increased insulin

secretion7. It also blocks histamine, serotonin and

cholinergic receptors

Clinical uses -Phenoxybenzamine

1. Pheochromocytoma: a catecholamine-secreting tumor of cells derived from the adrenal medulla

2. Raynaud; peripheral vascular disease

3. Autonomic hyperreflexia which predisposes paraplegics to strokes

4. BPH

Adverse effects Phenoxybenzamine

• Postural hypotension• Tachycardia it is contraindicated in patients

with decreased coronary perfusion.

• Sedation, fatigue• Nasal stuffiness• Miosis• Impotence (inhibits ejaculation)• Exercise care in hypovolemic patients.

Imidazoline derivatives – phentolamine (5-7hr)

produces a competitive block of α1 and α2-receptors.

1. Block serotonin receptors2. Stimulate H1 & H2

3. Stimulate M1; Parasympathomimetic

• Increased gastric motility & acid secretion• Increased secretion from exocrine glands, such

as salivary, sweat, lacrimal, pancreatic• Cardiac stimulation reflex and direct!!• it can be injected intracavernosally to produce

vasodilation of penile arteries (rarely used)

Alpha-1 selective blockers Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin

• the first three drugs are useful in the treatment of hypertension.

• Alfuzosin & Tamsulosin are indicated for the treatment of benign prostatic hypertrophy

• Prazosin (t1/2 3hrs): No significant tachycardia

Used in CHF and in hypertension but tolerance develops with time, may be due to fluid retention.• Adverse effects: First dose phenomenon.• Favorable effect on plasma lipids: increase

HDL/LDL ratio• Terazosin (t1/2 9-12 hrs)

Other α -adrenoceptor antagonists

• Indoramin: antihypertensive. • Urapidil is an α1 antagonist (its primary effect)

that also has weak α2-agonist and 5-HT1A-agonist actions and weak antagonist action at β1 receptors. It is used in Europe as an antihypertensive agent and for BPH.

• Labetalol has both α1-selective and β-antagonistic effects.

• Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but are also antagonists at α-receptors.

• Antidepressant: trazodone block α1 receptors.

a2 - selective antagonists Yohimbine

Chief active compound in Pausinystalia yohimbine (bark), Effects opposite of Clonidine

Enters CNS => increased sympathetic output => increased HR, BP, can cause severe tremors

Ingredient in many weight loss productsEnhances sexual activity – aphrodisiacBlocks other receptors: serotonin, dopamine,

Increases ADH releaseExperimental uses in Treatment of : 1. Raynaud's phenomenon to inhibit smooth

muscle contraction, 2. type 2 diabetes (α2 receptors inhibit insulin

secretion), 3. depression.

Therapeutic Uses ofAlpha-Adrenergic Blockers

• Hypertension - alpha-1 selective• Pheochromocytoma• Peripheral vascular disease –

Raynaud’s• Local Vasoconstrictor Excess• Benign prostatic hyperplasia• Erectile Dysfunction: Yohimbine or

intracavernous phentolamine + papaverine